Probing the Mouse Genome

Rick Woychik of the Biology Division can tell you almost anything you want to know about mouse genes. So, what does this have to do with sequencing the human genome? Well, as it turns out, there are a number of similarities (perhaps more than we'd like to admit) between mouse genes and human genes. And, as a practical matter, it's a lot easier to conduct a controlled study of a mouse in a lab than a man on the street.

Woychik looks at efforts to sequence the human genome as the first step in understanding how the genetic code actually works. "Once we've sequenced and analyzed all the DNA bases of the human genome," he says, "we will know where all the genes are, but we won't know what they do." Studying the mouse genome could provide some of the missing pieces of the genomic puzzle.

"If we determine the function of a particular mouse gene whose location we know," Woychik says, "we can often look at the corresponding area on a human chromosome and locate the functionally equivalent human gene."

One of the techniques Woychik uses to probe the mouse genome is known as insertional mutagenesis. In this technique, hundreds of identical pieces of DNA are injected into mouse zygotes (fertilized eggs) in the hope of creating mutations in the resulting offspring. The DNA fragments, or "transgenes," are then incorporated, seemingly at random, into the zygote's genetic code. More often than not, this process results in normal laboratory mice, but every so often an unusual variation in the appearance or physical structure of one of the offspring, such as malformed limbs or internal organs, suggests that a mutation has occurred. "When we see an abnormality in the appearance of the offspring," Woychik says, "we test to determine whether the gene that was interrupted by a transgene is responsible for the change in appearance."

Another technique used to investigate the function of various mouse genes is known as targeted mutagenesis. In contrast to the random mutations introduced by insertional mutagenesis, targeted mutagenesis allows researchers to determine the effect of introducing a mutation at a specific site on a selected gene.

This degree of accuracy is achieved by introducing changes in the chromosomal DNA of cultured embryonic cells using a process called homologous recombination. In this approach, altered genetic material is inserted back into the context of a living mouse by microinjecting the manipulated cells into a host blastocyst (a 4-day-old mouse embryo).

Uncovering all the functional parallels between the genes of mice and humans could easily occupy several research lifetimes, but Woychik and his group have a more modest goal. Says Woychik: "We hope we can begin to establish molecular connections between individual genes on the genome and specific developmental processes in both mice and men.

The Russells: A Family Affair

William Lawson (Bill) Russell and Liane Brauch (Lee) Russell, the eminent husband-and-wife team who have studied mammalian genetics for 45 years at ORNL's Biology Division, have much in common. Both received the International Roentgen Medal, both earned Ph.D. degrees in zoology and genetics from the University of Chicago, and both worked at the Jackson Memorial Laboratory in Bar Harbor, Maine, before coming to the Laboratory, where they have headed genetics research in the Biology Division. Also, both were elected to the National Academy of Sciences, one of only 11 couples so honored.

Bill Russell, the former scientific director of the Mammalian Genetics Section in the Biology Division and now an ORNL consultant, is a native of Newhaven, England, with a B.A. degree in zoology from Oxford University. Lee, head of the Mammalian and Genetics Development Section of the Biology Division since 1975, is a native of Vienna, Austria, with a B.A. degree in chemistry from Hunter College in New York City.

In 1947, Bill wanted to leave Jackson Memorial Laboratory but would only accept a new position if Lee were offered one, too. Alexander Hollaender, director of the new Biology Division at Clinton Laboratories, came through with such an offer, and Bill and Lee came to Oak Ridge in November 1947 shortly after Jackson Memorial Laboratory burned to the ground.

Bill's first achievement in Oak Ridge was to develop efficient and reliable genetic methods to determine the rate at which mouse genes are mutated by different types and levels of radiation. But, to do this, he had to set up the Mouse House, a national resource that contains more than a quarter million mice, for which he designed cages, food containers, racks, and machines for washing bottles and cages. Soon after experiments got under way, he found that the mutation rate in the mouse was 15 times that in the fruit fly. As a result, the National Council on Radiation Protection and Measurements reduced the permissible levels for occupational exposure to radiation.

In 1952, as a result of Lee's studies of the vulnerability of early embryos of irradiated mice, the Russells recommended that physicians use diagnostic X rays on the pelvic regions of childbearing women only during that part of the menstrual cycle when pregnancy cannot occur.

In 1958, the Russells and Elizabeth Kelly discovered that the mutation rate in mice exposed to chronic radiation (spread over time) was between one-third and one-fourth the mutation rate in mice exposed to acute radiation (delivered in a matter of minutes). It was a significant finding because no dose-rate effect had been found in fruit-fly studies and because it suggested that a genetic repair mechanism corrects minor damage caused by low doses of radiation. By the mid-1960s the Russells had proved that sensitivity to radiation differs not only between mice and fruit flies but also between male and female mice. They then started a new area of investigation: determining the genetic effects on mice of chemicals from drugs, fuels, and wastes. In 1971, Bill and his associates published a paper recommending that, based on mouse studies, the drug hycanthone should continue to be used as a therapeutic drug for schistosomiasis, a debilitating parasitic disease common in the Third World. In 1975, Lee developed a fur-spot test for identifying chemicals likely to be mutagenic in reproductive cells. In 1979, Bill found that the laboratory chemical ethylnitrosourea (ENU) is the most potent mutagen ever tested in mice, making it a prime tool for studying mechanisms of mutagenesis.

In the 1980s, while continuing her research on the effects of chemicals on mice, Lee enlarged her genetic studies on the nature of mutational lesions caused by different treatments. Under her leadership, her section has increased in scientific staff and moved into areas of modern molecular genetics, including insertional mutagenesis and targeted mutagenesis--techniques that alter random or selected mouse genes. The research may unlock the secrets of human DNA by locating specific genes responsible for specific functions or malfunctions, such as diseased kidneys. DOE has recently recognized the section's unique capability for adding to the genome research effort.

In 1991, the international journal Mutation Research dedicated a special issue to Bill on his 80th birthday. In their introduction, the journal's editors stated, "No single person has contributed more to the field of mammalian mutagenesis, and thus to genetic risk assessment in man, than Dr. W. L. Russell." They might have added that his accomplishments likely would have been half as impressive without the scientific research conducted by his wife. Together, the Russells have formed one of the most fruitful collaborations in the annals of American science.

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